Treatment of sunburn using analgesics and antihistamines

ABSTRACT

Combination compositions and kits comprising an analgesic and an antihistamine are provided as well as methods of use in treating sunburn.

CROSS-REFERENCES TO RELATED APPLICATIONS

The application claims the benefit of U.S. Provisional Application No.61/254,803, filed Oct. 26, 2009, incorporated herein by reference in itsentirety and for all purposes.

BACKGROUND OF THE INVENTION

Sunburn is a burn to the skin caused by ultraviolet (UV) radiation.Extended UV exposure can also lead to skin cancer. Sunburn oftenmanifests with one or more of the following symptoms: erythema(redness), pain, edema (swelling), itching, peeling, rash, warmth,nausea, headache, and fever. More severe sunburns can also causeblistering.

Available remedies for minor sunburn include topical anesthetics, suchas benzocaine, or topical wound care agents, such as aloe vera. Existingremedies, however, fail to adequately treat sunburns and the associatedsymptoms thereof. Sunburn is a very common malady for which there is noFDA approved therapy. Current data suggest that about 36% of all U.S.adults experience one or more sunburns each year. Thus, there is a needin the art for effective medications for the treatment of sunburns. Thepresent invention meets these and other needs in the art.

BRIEF SUMMARY OF THE INVENTION

The present inventors have discovered that the combination of ananalgesic (e.g. an NSAID or over-the-counter analgesic) and anantihistamine is effective to treat sunburn. The combination compositionprovides a safe, effective, and convenient treatment for sunburn.

In one aspect, a method of treating a sunburn in a subject (e.g. a humansubject) in need of such treatment is provided. The method includesadministering to the subject a combined therapeutically effective amountof an analgesic (e.g. over-the-counter analgesic) and an antihistamine.

In another aspect, a kit is provided for the treatment of a sunburn(e.g. of a human). The kit includes a dispensing apparatus having aplurality of analgesic dosage units and a plurality of antihistaminedosage units.

In another aspect, a combination composition product for treatment of asunburn (of a human) in a subject in need such treatment is provided.The combination composition product includes effective amounts of ananalgesic (e.g. over-the-counter analgesic) and an antihistamine.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawings are provided for demonstrative purposes only and are notnecessarily drawn to scale. No attempt is made to show structuralfeatures in more detail than may be necessary for a fundamentalunderstanding of the invention. For ease of demonstration, the analgesic(e.g., an NSAID) is designated “N”, the antihistamine is designated“AH,” and the combination of an analgesic and an antihistamine isdesignated “NAH.”

FIGS. 1A-1B depict exemplary dispensers having a row-and-columnconfiguration with analgesic blisters and antihistamine blisters. FIG.1A depicts a configuration wherein each dose, indicated by perforations,includes one analgesic dosage unit and one antihistamine dosage unit.FIG. 1B depicts a configuration wherein each dose, indicated byperforations, includes more than one analgesic dosage unit and oneantihistamine dosage unit.

FIGS. 2A-2C depict exemplary dispenser apparatuses configured to ejectboth active agents at once. FIG. 2A depicts combination blisterscontaining co-formulated analgesic and antihistamine. FIG. 2B depictscombination blisters including a partition separating individuallyformulated active agents. FIG. 2C depicts a snap-lid type dispenserapparatus configured to dispense individually formulated active agents.

FIG. 3 depicts an exemplary dispenser configuration featuringindications (text and perforations) for BID dosing and a treatmentduration of 3 days.

FIG. 4 depicts an exemplary dispenser configuration featuring QID dosingof an analgesic and an antihistamine for 4 days. After each combinationdose, a follow up dose of analgesic (N′) may be administered.

FIGS. 5A-5B depict kits including two blister packs: a first blisterpack for dispensing an OTC analgesic (FIG. 5A), and a second blisterpack for dispensing an antihistamine (FIG. 5B). The first and secondblister packs are distinguishable within the kit by, e.g., shading asshown. This exemplary kit features QID dosing for 4 days.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

In some embodiments, the composition is used to treat a disease, e.g., asunburn such as an acute sunburn. “Treating” the disease includes one ormore of: addressing a physiological cause of the disease, addressing aphysiological cause of a disease symptom, reducing the severity of thedisease, ameliorating a symptom of the disease, and shortening theduration of the disease (e.g. decreasing recovery time from a sunburn).Therefore, treating a sunburn includes relief (e.g. temporary relief) ofpain or discomfort due to mild to moderate sunburn and relief (e.g.temporary relief) of redness due to mild or moderate sunburn.

The “subject” as used herein is a subject in need of treatment forsunburn. The subject is preferably a human, but also may includelaboratory, pet, domestic, or livestock animals. In one embodiment, thesubject is a mammal having at least some portion of exposed or partiallyexposed skin that is not completely shielded from radiation by hair(such as a human or a hairless rat, mouse, or dog).

The term “combined therapeutically effective amount” means that theactive agents, when co-administered, are effective to treat sunburn. Theamount of one active agent may be insufficient to treat a sunburn in theabsence of the second active agent, but together they aretherapeutically effective.

The term “individually therapeutically effective amount” means an amountof a single active agent that, when administered, is effective to treatsunburn. The efficacy of an individually effective amount of an activeagent can be supplemented with, or synergistically enhanced by, theaddition of the second active agent. The second active agent may beadministered in an individually therapeutically effective amount or aspart of a combined therapeutically effective amount.

The term “substantially free” means that the specified component iseither entirely absent, or it is present in an amount too small tocontribute to therapeutic efficacy, either alone or in combination withthe other active agents.

The term “co-administer” means to administer more than one active agent,such that the duration of physiological effect of one active agentoverlaps with the physiological effect of a second active agent. Forsystemic agents, the term co-administer means that more than one activeagent is present in the bloodstream during at least one time point. Insome embodiments, co-administration includes administering one activeagent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a secondactive agent. Co-administration includes administering two active agentssimultaneously, approximately simultaneously (e.g., within about 1, 5,10, 15, 20, or 30 minutes of each other), or sequentially in any order.In some embodiments, co-administration can be accomplished byco-formulation, i.e., preparing a single dosage unit including bothactive agents. In other embodiments, the active agents can be formulatedseparately. In some embodiments, each active agent is formulatedseparately, but administered approximately simultaneously.

A “dosage unit” is a discrete item for administration, such as a tabletor capsule. For a liquid dosage form, the dosage unit may be, e.g., ateaspoon, tablespoon, or dosing cup amount of the liquid formulation.

The term “dose” is the amount of active agent to be administered at onetime. The dose may be present in a single dosage unit, or it may bedivided among more than one dosage unit. For example, a dose of 400 mgibuprofen may be administered as a single 400 mg tablet, or it may beadministered as two 200 mg tablets.

The “daily dose” is the amount of active agent that is to beadministered per day (i.e., any 24 hour period). The daily dose caninclude one or more doses. For example, a daily dose of 600 mg ibuprofencan be administered as a single 600 mg dose, or three 200 mg doses.

The “treatment dose” is the amount of active agent that is to beadministered during a course of treatment. The treatment dose mayinclude one or more doses that may be the same as or different from oneanother. For example, the treatment regimen may include a titrationperiod of increasing doses and/or a weaning period of decreasing doses.

The term “and/or” as used herein indicates that one or more of thestated cases may occur.

II. Combination Compositions

A. Active Agents

Provided herein are combination compositions including an analgesic(e.g. over-the-counter (OTC) analgesic) and an antihistamine. Theanalgesic and antihistamine may be co-formulated to form at least aportion of a single dosage unit, or they may be individually formulatedto form separate dosage units. The combination composition may beformulated for oral administration. The combination compositions areparticularly useful for treating sunburn as described in detail furtherbelow.

Unless otherwise noted, the analgesic (e.g. OTC analgesic) and/or theantihistamine active agents may be present as free agents or as apharmaceutically acceptable salts. For example, chlorpheniramine may bepresent as a maleate salt.

An analgesic is a pain-relieving active agent, such as acetaminophen oran NSAID. An over-the-counter (OTC) analgesic is an analgesic available,for at least one dose strength, without a prescription. In particular,an OTC analgesic is any pain-relieving active agent that, for at leastone dose strength, is approved by the U.S. Food and Drug Administrationprior to Oct. 26, 2009 for administration without a prescription from ahealth care professional. The OTC analgesic can be, for example,acetaminophen (paracetamol, APAP) or a non-steroidal anti-inflammatorydrug (NSAID) such as ibuprofen.

In one embodiment, the analgesic is an NSAID. In some embodiments, theNSAID is an OTC NSAID. An NSAID is a non-steroidal anti-inflammatorydrug. An NSAID typically has analgesic, antipyretic, and/oranti-inflammatory effects. Acceptable NSAIDs include, but are notlimited to: an ibuprofen, an aspirin, a naproxen, a diclofenac, alicofelone, omega-3 fatty acids, a COX-2 inhibitor (e.g., celecoxib), asulphonanilide (e.g., nimesulide), an indomethacin, and combinationsthereof. In some embodiments, the NSAID is an aspirin, an ibuprofen, ora naproxen. In some embodiments, the NSAID is an ibuprofen. In anotherembodiment, the NSAID is racemic ibuprofen (i.e., (S)- and(R)-ibuprofen).

An antihistamine is an agent that inhibits the release or action ofhistamine. Useful antihistamines include, but are not limited to,H₁-receptor antagonists and/or H₂-receptor antagonists. In someembodiments, the H₁-receptor antagonist is a chlorpheniramine, adiphenhydramine, a loratadine, a desloratadine, a meclizine, aquetiapine, a fexofenadine, a pheniramine, a cetirizine, a promethazine,and a levocetirizine. Useful H₂-receptor antagonists may include acimetidine, a famotidine, a ranitidine, a nizatidine, a roxatidine, or alafutidine, and combinations thereof. In some embodiments, theantihistamine is an H₁-receptor antagonist. In some embodiments, theantihistamine is a chlorpheniramine.

In some embodiments, the antihistamine is chlorpheniramine, and theanalgesic is an NSAID. In related embodiments, the antihistamine ischlorpheniramine, and the analgesic is an ibuprofen. In one embodiment,the antihistamine is a chlorpheniramine, and the analgesic is a racemicibuprofen.

In some embodiments, the combination composition is substantially freeof any additional active agent not specifically recited. For example, insome embodiments where the combination composition is stated to includechlorpheniramine and ibuprofen, the composition is substantially free ofany additional active agents. In certain embodiments, the combinationcomposition is substantially free of any additional oral active agentnot specifically recited. In other embodiments, the combinationcomposition is substantially free of any additional synthetic activeagent (i.e., an active agent that is not found in nature, but rather ismade synthetically) not specifically recited. In another embodiment, thecombination composition is substantially free of any additional activeagent used for treating sinus symptoms (e.g., cold, flu, or allergysymptoms). Such active agents useful for treating sinus symptoms thatmay be excluded for the combination compositions provided herein includedecongestants (e.g., pseudoephedrine, phenylephrine,phenylpropanolamine, oxymetazoline), steroids (e.g., cortisone,dexamethasone, hydrocortisone, prednisone), epinephrine, theophylline,anti-tussives (e.g., opiates such as codeine, dextromethorphan),expectorants (e.g., guaifenesin), anti-leukotrienes (e.g., montelukast),anti-cholinergics (e.g., ipratropium, oxitropium, tiotropium), and mastcell stabilizers (e.g., cromolyn and nedocromil). In some embodiments,the combination composition is substantially free of pseudoephedrine.

In another embodiment, the combination composition may include one ormore additional active agents (i.e. agents other than the recitedanalgesic and antihistamine). In one embodiment, the one or moreadditional active agent is administered topically. In one embodiment,the combination composition includes an additional active agent usefulfor treating burns. Exemplary additional active agents include topicalanesthetics (e.g., benzocaine, lidocaine), topical wound care agents(e.g., aloe), topical anti-pruritic agents (e.g., calamine), topicalmoisturizers (e.g., vitamin E, dimethicone, oatmeal), topical debridingagents, and topical or systemic anti-infectives (e.g., antibacterialagents, antifungal agents, silver sulfadiazine, bacitracin, neomycin,polymyxin B, aminoglycosides). In one embodiment, the additional activeagent is a natural active agent such as oatmeal or aloe. In certainembodiments, a single additional active agent is present (and no otheractive agents are present). In other embodiments, two additional activeagents are present (and no other active agents are present). In otherembodiments, three additional active agents are present (and no otheractive agents are present). In other embodiments, four additional activeagents are present (and no other active agents are present). In otherembodiments, five additional active agents are present (and no otheractive agents are present).

In another embodiment, there is provided a combination compositionproduct (e.g. an oral combination composition product, parenteralcombination composition product or a topical composition product) fortreatment of a sunburn in a subject in need of such treatment. Thecombination composition product includes: (i) 16-20 analgesic dosageunits (e.g. an oral analgesic dosage units, parenteral analgesic dosageunits or topical analgesic dosage units) and 16-20 antihistamine dosageunits (e.g. an oral antihistamine dosage units, parenteral antihistaminedosage units or topical antihistamine dosage units). In some embodimentsthe combination product includes: (i) 16-20 ibuprofen dosage units (e.g.an oral ibuprofen dosage units, parenteral ibuprofen dosage units ortopical ibuprofen dosage units), each containing about 50 mg to about800 mg of ibuprofen (or other specific dosages described below), or apharmaceutically acceptable salt thereof; and (ii) 16-20chlorpheniramine dosage units (e.g. an oral chlorpheniramine dosageunits, parenteral chlorpheniramine dosage units or topicalchlorpheniramine dosage units), each containing about 50 mg to about 800mg of ibuprofen (or other specific dosages described below), eachcontaining about 1 mg to about 8 mg of chlorpheniramine (or otherspecific dosages described below), or a pharmaceutically acceptable saltthereof. The dosage units may be suitable for administering 2-6 times(e.g. 3, 4 or 5 times) per day. The analgesic (e.g. ibuprofen) dosageunits and the antihistamine (e.g. chlorpheniramine) dosage units may besubstantially free of additional active agents (e.g. synthetic activeagent). In some embodiments, the dosage units are oral dosage units. Incertain embodiments, 16, 17, 18, 19 or 20 dosage units are provided.

In one embodiment, there is provided a combination composition product(e.g. an oral combination composition product, parenteral combinationcomposition product or a topical composition product) for treatment of asunburn in a subject in need such treatment. The combination compositionproduct includes 16-20 dosage units, each containing an analgesic (e.g.NSAID) and an antihistamine. In some embodiments, the combinationcomposition product includes 16-20 dosage units, each containing about50 mg to about 800 mg of ibuprofen (or other specific dosages describedbelow) and about 1 mg to about 8 mg of chlorpheniramine (or otherspecific dosages described below). The dosage units are suitable foradministering 3-6 times per day (e.g. 4 or 5). In some embodiments, eachof the dosage units are substantially free of additional active agents(e.g. synthetic active agents). In some embodiments, the dosage unitsare oral dosage units. In certain embodiments, 16, 17, 18, 19 or 20antihistamine and/or analgesic dosage units are provided.

In one embodiment, there is provided a combination composition product(e.g. an oral combination composition product, parenteral combinationcomposition product or a topical composition product) for treatment of asunburn in a subject in need of such treatment. The combination productincludes a minimum of 3 and a maximum of 40 dosage units. Each dosageunit comprises an analgesic (e.g. NSAID) dose and an antihistamine dose.In some embodiments, each of the dosage units are substantially free ofadditional active agents (e.g. synthetic active agents). In someembodiments, the dosage units are oral dosage units. In certainembodiments, 5-35 dosage units, 10-30, 15-25 or about 20 dosage unitsare provided. In certain embodiments, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,. 27, 28, 29, 30,31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 dosage units are provided.

In one embodiment, there is provided a combination composition product(e.g. an oral combination composition product, parenteral combinationcomposition product or a topical composition product) for treatment of asunburn in a subject in need of such treatment. The combination productincludes a minimum of 3 and a maximum of 40 analgesic (e.g. NSAID)dosage units. In some embodiments, each analgesic (e.g. NSAID) dosageunit includes a dose of a ibuprofen. Also included is a minimum of 3 anda maximum of 40 antihistamine dosage units. In some embodiments,antihistamine dosage unit includes a dose of an chlorpheniramine. Insome embodiments, the analgesic and antihistamine dosage units aresubstantially free of additional active agents (e.g. synthetic activeagents). In some embodiments, the dosage units are oral dosage units. Incertain embodiments, 5-35 antihistamine and/or analgesic dosage units,10-30, 15-25 or about 20 dosage units are provided. In certainembodiments, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,37, 38, 39 or 40 antihistamine and/or analgesic dosage units areprovided.

In one embodiment, the combination composition product (e.g. an oralcombination composition product, parenteral combination compositionproduct or a topical composition product) includes: (i) a minimum of 4and a maximum of 32 analgesic (e.g. NSAID) dosage units; and a minimumof 4 and a maximum of 16 antihistamine dosage units. In someembodiments, the dosage units are oral dosage units. In certainembodiments, 10-30, 15-25 or about 20 analgesic dosage units areprovided. In certain embodiments, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17,. 18, 19, 20, 21, 22, 23, 24, 25, 26,. 27, 28, 29, 30,31, or 32 analgesic dosage units are provided. In some embodiments, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 antihistamine dosage unitsare provide (e.g. 8-12, about 10 or about 14). In some embodiments, theanalgesic and antihistamine dosage units are substantially free ofadditional active agents (e.g. synthetic active agents).

In another embodiment, the combination composition product (e.g. an oralcombination composition product, parenteral combination compositionproduct or a topical composition product) contains: (i) a minimum of 4and a maximum of 16 first analgesic (e.g.

NSAID) dosage units. In some embodiments, each first analgesic dosageunites comprises about 200 mg ibuprofen. The combination compositionproduct also includes a minimum of 4 and a maximum of 16 antihistaminedosage units. In some embodiments, each antihistamine dosage unitcomprises 2-4 mg chlorpheniramine. The combination composition productalso includes a minimum of 4 and a maximum of 16 second analgesic (e.g.NSAID) dosage units, wherein each of the second analgesic dosage unitshave less analgesic than each of the first analgesic dosage unites. Insome embodiments, each of the second analgesic dosage units includeabout 100 mg ibuprofen. In some embodiments, the dosage units are oraldosage units. In some embodiments, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, or 16 each of the dosage units are provide (e.g. 8-12, about 10 orabout 14). In some embodiments, each of the dosage units aresubstantially free of additional active agents (e.g. synthetic activeagents). In some embodiments, the dosage units are oral dosage units.

In some embodiments of the combination compositions provided herein, theNSAID is an aspirin, an ibuprofen, a naproxen, or a pharmaceuticallyacceptable salt thereof. In another embodiment of the combinationcomposition, the NSAID is a racemic ibuprofen, or a pharmaceuticallyacceptable salt thereof.

In one embodiment of the combination compositions, the antihistamine isan H₁-receptor antagonist antihistamine, such as a diphenhydramine, aloratadine, a desloratadine, a meclizine, a quetiapine, a fexofenadine,a pheniramine, a cetirizine, a promethazine, a chlorpheniramine, alevocetirizine, or a pharmaceutically acceptable salt thereof. In oneembodiment, the antihistamine is a chlorpheniramine, or apharmaceutically acceptable salt thereof.

In one embodiment of the combination composition, the antihistamine is achlorpheniramine, or a pharmaceutically acceptable salt thereof, and theNSAID is a racemic ibuprofen, or a pharmaceutically acceptable saltthereof.

In one embodiment, an analgesic dosage unit includes about 600 mg of aracemic ibuprofen, or a therapeutically equivalent amount of apharmaceutically acceptable salt thereof, and an antihistamine. In oneembodiment, the dosage unit is substantially free of an additional anactive agent (e.g. a synthetic active agent). In one embodiment, theantihistamine is a chlorpheniramine, or a pharmaceutically acceptablesalt thereof. In one embodiment, the dosage unit includes about 4 mg ofchlorpheniramine, or a therapeutically equivalent amount of apharmaceutically acceptable salt thereof.

In one embodiment, a combination composition is provided which includes:(i) a first oral dosage unit including about 600 mg of an ibuprofen, ora therapeutically equivalent amount of a pharmaceutically acceptablesalt thereof; and (ii) a second oral dosage unit including anantihistamine. The combination composition may be substantially free ofan additional active agent (e.g. a synthetic active agent). In someembodiments, the antihistamine is a chlorpheniramine, or apharmaceutically acceptable salt thereof. In another embodiment, thesecond oral dosage unit includes about 4 mg of the chlorpheniramine, ora therapeutically equivalent amount of a pharmaceutically acceptablesalt thereof.

In some embodiments, the combination composition includes co-packagedindividual tablets of ibuprofen (200 or 400 mg) and chlorpheniraminemaleate (2 or 4 mg). In related embodiments, the route of administrationis oral. Therefore, the combination composition may include an oralcombination composition dosage units (e.g. tablets). Dosing may be every4 hours for the 200 mg ibuprofen regimen and every 8 hours for the 400mg regimen.

B. Pharmaceutical Formulation

The combination composition can further include one or morepharmaceutically acceptable excipients. A “pharmaceutically acceptableexcipient” includes pharmaceutically and physiologically acceptable,organic or inorganic carrier substances suitable for enteral orparenteral administration that do not deleteriously react with theactive agent. A “pharmaceutically acceptable excipient,” as used herein,excludes active agents. Suitable pharmaceutically acceptable carriersinclude water, salt solutions (such as Ringer's solution), alcohols,oils, gelatins, and carbohydrates such as lactose, amylose or starch,fatty acid esters, hydroxymethylcellulose, and polyvinyl pyrrolidone.Such preparations can be sterilized and, if desired, mixed withauxiliary agents such as lubricants, preservatives, stabilizers, wettingagents, emulsifiers, salts for influencing osmotic pressure, buffers,coloring, and/or aromatic substances and the like that do notdeleteriously react with the active agent.

The combination composition may include, for example, a mixture of ananalgesic (e.g. NSAID), an antihistamine, and one or morepharmaceutically acceptable excipients. The mixture can be compressedinto a tablet or filled into a capsule shell.

In another embodiment, the pharmaceutical formulation may contain twomixtures: a first mixture including an analgesic (e.g. NSAID) and one ormore pharmaceutically acceptable excipients, and a second mixtureincluding an antihistamine and one or more pharmaceutically acceptableexcipients. The two mixtures can be compressed together (e.g., to form atablet having a bi-layer or core/coat structure). Alternatively the twomixtures can be individually compressed to form separate analgesic (e.g.NSAID) dosage units and antihistamine dosage units.

In the pharmaceutical formulations described herein, the active agentsmay be in physical contact with one another (e.g., in admixture).Alternatively, the active agents may by physically separated (e.g., bycoating granules of one or both active agents with a barrier coatingbefore mixing, or by a barrier layer between tablet layers). In oneembodiment, only one portion or layer of the dosage form contains activeagent(s). In one embodiment, the active agent(s) is present as a uniformmixture. In another embodiment, more than one portion or layer of thedosage form contains active agent(s).

The combination composition can be formulated for any route ofadministration, including enteral, oral, sublingual, buccal, parenteral,intravenous, and topical routes. In one embodiment, the combinationcomposition is formulated for oral administration.

The pharmaceutically acceptable carrier can be either solid or liquid.Solid form preparations include powders, tablets (including chewabletablets), pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier may also act as a diluent, flavoring agent,binder, preservative, tablet disintegrating agent, or encapsulatingmaterial.

In powders, the carrier is a finely divided solid in a mixture with thefinely divided active component. In tablets, the active component ismixed with the carrier having the necessary binding properties insuitable proportions and compacted in the shape and size desired.

The powders and tablets preferably contain from 5% to 70% of the activecompound. Suitable carriers are magnesium carbonate, magnesium stearate,talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth,methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoabutter, and the like. The term “preparation” is intended to include theformulation of the active compound with encapsulating material as acarrier providing a capsule in which the active component with orwithout other carriers, is surrounded by a carrier, which is thus inassociation with it. Similarly, cachets and lozenges are included.Tablets, powders, capsules, pills, cachets, and lozenges can be used assolid dosage units suitable for oral administration.

Liquid oral formulations, e.g., aqueous suspensions, can be prepared bydissolving the active agent in water and adding suitable colorants,flavors, stabilizers, and thickening agents as desired. Aqueoussuspensions suitable for oral use can be made by dispersing the finelydivided active agent in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,and other well-known suspending agents.

In one embodiment, the analgesic (e.g. OTC analgesic) and/or theantihistamine is formulated as an oral dosage form, e.g., tablet,caplet, capsule, softgel, or oral suspension. In another embodiment, theanalgesic (e.g. OTC analgesic) and/or the antihistamine is formulated asa tablet, caplet, capsule, or softgel (a liquid formulation encapsulatedby a soft gelatin shell). In yet another embodiment, the analgesic (e.g.OTC analgesic) and/or the antihistamine is formulated as a solid oralunit dosage form.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

Active agents may have limited solubility in water and therefore mayrequire a surfactant or other appropriate co-solvent in the composition.Such co-solvents include: Polysorbate 20, 60, and 80; Pluronic F-68,F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil. Suchco-solvents are typically employed at a level between about 0.01% andabout 2% by weight.

Viscosity greater than that of simple aqueous solutions may be desirableto decrease variability in dispensing the formulations, to decreasephysical separation of components of a suspension or emulsion offormulation, and/or otherwise to improve the formulation. Such viscositybuilding agents include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxypropyl methylcellulose,hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropylcellulose, chondroitin sulfate and salts thereof, hyaluronic acid andsalts thereof, and combinations of the foregoing. Such agents aretypically employed at a level between about 0.01% and about 2% byweight.

In one embodiment, the analgesic (e.g. OTC analgesic) is formulated forimmediate release. In another embodiment, the antihistamine isformulated for immediate release. In another embodiment, both activeagents are formulated (together or separately) for immediate release.

In other embodiments, the pharmaceutical formulations may additionallyinclude components to provide modified, sustained, extended, delayed, orpulsatile release. Release modification can be achieved byrelease-modifying coatings and/or matrices. Exemplary components includehigh molecular weight, anionic mucomimetic polymers, gellingpolysaccharides, and finely-divided drug carrier substrates. Thesecomponents are discussed in greater detail in U.S. Pat. Nos. 4,911,920;5,403,841; 5,212,162; and 4,861,760. The entire contents of thesepatents are incorporated herein by reference in their entirety for allpurposes.

C. Dosage and Administration

The combination composition is prepared in a dose that istherapeutically effective to treat sunburn. In one embodiment, thecombination composition includes a combined therapeutically effectiveamount of the analgesic (e.g. OTC analgesic) and antihistamine. In thiscase, the dosage of one active agent may be insufficient to treat asunburn in the absence of the second active agent, but together they aretherapeutically effective. In one embodiment, the analgesic (e.g. OTCanalgesic) dose is therapeutically insufficient withoutco-administration of the antihistamine. In another embodiment, theantihistamine dose is therapeutically insufficient withoutco-administration of the analgesic (e.g. OTC analgesic).

In another embodiment, one or both active agents (i.e. the analgesic andthe antihistamine) are present in an individually therapeuticallyeffective amount. In this case, one or both active agents are present inan amount that is sufficient to treat sunburn, but the therapeuticeffect is increased or synergistically enhanced by administering bothactive agents. In one embodiment, the combination composition includesan individually therapeutically effective amount of an analgesic (e.g.OTC analgesic). In another embodiment, the combination compositionincludes an individually therapeutically effective amount of anantihistamine. In yet another embodiment, the combination compositionincludes both an individually therapeutically effective amount of ananalgesic (e.g. OTC analgesic) and an individually therapeuticallyeffective amount of an antihistamine.

The appropriate dose, frequency, and duration can be modified to addressthe particular needs of a particular subject by taking into accountfactors including, but not limited to, the age, gender, weight, andhealth of the subject; the severity, extent (e.g., surface area), andlocation of the burn; and the duration of, and time elapsed since UVexposure.

In the combination compositions described herein, the analgesic (e.g.OTC analgesic) may be present in a dose amount approved foradministration by the FDA (e.g. OTC administration), or it may bepresent in a dose amount that is higher or lower than an

FDA approved dose for administration (e.g. OTC administration). In someembodiments, the analgesic (e.g. OTC analgesic) is present in a doseamount that is equal to an FDA-approved dose (e.g. OTC dose). In yetanother embodiment, the analgesic (e.g. OTC analgesic) is present in adose amount that is within the range of FDA-approved doses (e.g. OTCdoses). In some embodiments, the analgesic (e.g. OTC analgesic) doseamount is more than 75%, at least 100%, or more than 100% of anFDA-approved dose (e.g. OTC dose). The FDA-approved doses referred to inthis paragraph are those approved as of Oct. 26, 2009.

In some embodiments, the analgesic is acetaminophen. The acetaminophendose amount may be about 100 mg to about 4000 mg, about 80 mg to about160 mg, about 325 mg to about 650 mg, about 325 mg to about 500 mg, orabout 500 mg to about 1000 mg. In some embodiments, the acetaminophendose is about 325 mg, about 500 mg, or about 650 mg. In someembodiments, the acetaminophen daily dose is about 100 mg to about 4000mg, about 325 mg to about 500 mg, about 650 mg to about 1000 mg, orabout 975 mg to about 1500 mg.

In some embodiments, the analgesic is an NSAID. The NSAID (e.g.ibuprofen) dose amount may be about 50 mg to about 800 mg, about 50 mgto about 600 mg, about 200 mg to about 600 mg, about 200 mg to about 400mg, or about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, orabout 2000 mg. In another embodiment, the amount of NSAID is about 50mg, about 100 mg, about 200 mg, about 400 mg, or about 600 mg. In oneembodiment, the NSAID dose is about 100 mg ibuprofen, 150 mg ibuprofen,about 200 mg ibuprofen, about 250 mg ibuprofen, about 300 mg ibuprofen,about 350 mg ibuprofen, about 400 mg ibuprofen, about 450 mg ibuprofen,about 500 mg ibuprofen, about 550 mg ibuprofen, about 600 mg ibuprofen,about 650mg ibuprofen, about 700 mg ibuprofen, about 750 mg ibuprofen,about 800 mg ibuprofen, about 850 mg ibuprofen, about 900 mg ibuprofen,about 950 mg ibuprofen, or about 1000 mg ibuprofen. In one embodiment,the NSAID dose is about 200 mg ibuprofen. In another embodiment, theNSAID dose is about 400 mg ibuprofen. In another embodiment, the NSAIDdose is about 600 mg ibuprofen. In one embodiment, the NSAID dose isabout 600 mg of racemic ibuprofen, or a therapeutically equivalentamount of a pharmaceutically acceptable salt thereof.

The NSAID dose amount may be present in a single dosage unit, or it maybe divided among more than one dosage unit. For example, in oneembodiment, the combination composition includes an NSAID dosage unitcontaining about 200 mg ibuprofen. In another embodiment, the NSAIDdosage unit contains about 400 mg ibuprofen. In yet another embodiment,the NSAID dosage unit contains about 600 mg ibuprofen. In someembodiments, the NSAID daily dose is about 50 mg to about 3200 mg, about50 mg to about 2000 mg, about 200 mg to about 1800 mg, about 400 mg toabout 1600 mg, about 600 mg to about 1200 mg, or about 200 mg, about 400mg, about 600 mg, about 800 mg, or about 1000 mg per 24 hours. Theseexemplary NSAID amounts are particularly suitable when the NSAID isibuprofen. Adjustments may be made as necessary for various salt formsor alternative NSAIDs.

In some embodiments, the antihistamine (e.g. chlorpheniramine) doseamount is about 1 mg to about 10 mg, about 1 mg to about 8 mg, about 2mg to about 8 mg, about 2 mg to about 6 mg, about 2 mg to about 4 mg, orabout 2 mg, about 4 mg, about 6 mg, or about 8 mg. In one embodiment,the antihistamine dose is about 1 mg, about 2 mg, about 3 mg, about 4mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10mg chlorpheniramine. In one embodiment, the antihistamine dose is about2 mg chlorpheniramine. In another embodiment, the antihistamine dose isabout 4 mg chlorpheniramine. In yet another embodiment, theantihistamine dose is about 6 mg chlorpheniramine. In yet anotherembodiment, the antihistamine dose is about 8 mg chlorpheniramine. Insome embodiments, the antihistamine dose amount is more than 75%, atleast 100%, or more than 100% of an FDA approved dose (e.g. OTC dose) asof Oct. 26, 2009.

The antihistamine dose amount may be present in a single dosage unit, orit may be divided among more than one dosage unit. In some embodiments,the antihistamine daily dose is about 2 mg to about 50 mg, about 2 mg toabout 24 mg, about 2 mg to about 16 mg, or about 2 mg to about 8 mg,about 2 mg, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12mg, about 14 mg, or about 16 mg per 24 hours. These exemplary amountsare particularly suitable when the antihistamine is chlorpheniramine.One of ordinary skill in the art could adjust as necessary for varioussalt forms or alternative antihistamines.

In one embodiment, the combination composition includes about 50, 200,400, 600, or 800 mg of ibuprofen and about 2, 4, 6 or 8 mgchlorpheniramine. In another embodiment, the combination compositionincludes about 200, 400, or 600 mg of ibuprofen and about 2, 4, or 8 mgchlorpheniramine. In another embodiment, the combination compositionincludes about 200 or 400 mg ibuprofen and about 2 or 4 mgchlorpheniramine. In another embodiment, the combination compositionincludes about 200 mg ibuprofen and about 2 mg chlorpheniramine. Inanother embodiment, the combination composition includes about 400 mgibuprofen and about 4 mg chlorpheniramine. In another embodiment, thecombination composition includes about 600 mg ibuprofen and about 4 mgchlorpheniramine. In yet another embodiment, the combination compositionincludes about 200 mg ibuprofen and about 4 mg chlorpheniramine. In yetanother embodiment, the combination composition includes about 400 mgibuprofen and about 2 mg chlorpheniramine.

In some embodiments, the combination composition is administered aboutevery 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7,6, 5, 4, 3, 2 or 1 hour(s). In one embodiment, the combinationcomposition is administered about every 24, 12, 8, 6, or 4 hours. In yetanother embodiment, the combination composition is administered every 8or 12 hours. In some embodiments, the combination composition isadministered 2, 3, 4, 5, or 6 times during at least one 24 hour period.In another embodiment, the combination composition is administered 2 or3 times during at least one 24 hour period. In some embodiments, thecombination composition is administered two times per day (BID), threetimes per day (TID), four times a day (QID), five time per day, or sixtimes per day.

In some embodiments, administration of the combination compositionincludes simultaneous or approximately simultaneous administration ofboth active agents, whether co-formulated or individually formulated.However, staggered administration is also contemplated, whereby at leastone dose of an active agent is administered sequentially. For example,one active agent may be administered once a day, while the other activeagent is administered twice a day.

A staggered dosing regimen is exemplified by FIG. 4. A staggered dosingregimen can include administering a combination of an analgesic (e.g.OTC analgesic) and antihistamine, and administering an optional followup dose of an analgesic (e.g. OTC analgesic). Thus, the analgesic (e.g.OTC analgesic) may be administered more frequently (e.g., twice asfrequently) as the antihistamine. The combination dose may be separatelyformulated and co-administered (as pictured) or co-formulated (notshown). The following table describes an exemplary staggered dosingschedule for one day (t=0-24 hours). In one embodiment, the dosingregimen is administered for 1, 2, 3, or 4 days.

TABLE 1 QID Staggered Dosing Schedule Time (h) Dose  8 am 0 N (200 mg)AH (2 to 4 mg) 10 am 2 N (100 mg) 12 pm 4 N (200 mg) AH (2 to 4 mg)  2pm 6 N (100 mg)  4 pm 8 N (200 mg) AH (2 to 4 mg)  6 pm 10 N (100 mg)  8pm 12 N (200 mg) AH (2 to 4 mg) 10 pm 14 N (100 mg) N = analgesic (e.g.OTC analgesic); AH = antihistamine

In one aspect, the combination composition is administered over asufficient number of days to treat the sunburn of a subject. In someembodiments, the combination composition is administered for 1, 2, 3, 4,5, 6, or 7 days, preferably consecutive days. In another embodiment, thecombination composition is administered for 2 to 6 days. In anotherembodiment, the combination composition is administered for 2 to 5 days.In another embodiment, the combination composition is administered for 3to 5 days. In another embodiment, the combination composition isadministered for 3 to 4 days. In another embodiment, the combinationcomposition is administered for at least 3 consecutive days. In anotherembodiment, the combination composition is administered for at least 2consecutive days. In another embodiment, the combination composition isadministered for no more than 3 consecutive days. In another embodiment,the combination composition is administered for no more than 2consecutive days.

The combination composition can be provided as a combination productincluding a plurality of analgesic (e.g., NSAID) doses and a pluralityof antihistamine doses. In some embodiments, the combination product caninclude co-formulated active agents. For example, the product mayinclude a plurality of combination dosage units, wherein the combinationdosage unit contains both an NSAID and an antihistamine. In otherembodiments, the combination product includes individually formulatedactive agents. For example, the product can include a plurality of NSAIDdosage units (containing an NSAID but no antihistamine) and a pluralityof antihistamine dosage units (containing an antihistamine but noNSAID.) In any of these embodiments, the combination product can besubstantially free of any additional active agent, any additional oralactive agent, any additional synthetic active agent, and/or anyadditional active agent for treating sinus symptoms.

In one embodiment, the analgesic (e.g., NSAID) dosage units and theantihistamine dosage units are visibly distinguishable by size, shape,color, etc.

In one embodiment, the number of analgesic (e.g., NSAID) doses and thenumber of antihistamine doses are independently selected from a minimumof 3 to a maximum of 40, about 3 to about 6, about 18 to about 36, about6 to about 12, about 9 to about 18, about 16 to about 20, or about 18doses. The number of analgesic (e.g., NSAID) doses may be the same as ordifferent from the number of the antihistamine doses. In one embodiment,the number of analgesic (e.g., NSAID) doses is the same as the number ofthe antihistamine doses. In one embodiment, the analgesic (e.g., NSAID)doses and the antihistamine doses are co-formulated. In anotherembodiment, the analgesic (e.g., NSAID) doses and the antihistaminedoses are co-administered.

In another embodiment, the number of analgesic (e.g., NSAID) dosageunits and the number of antihistamine dosage units are independentlyselected from a minimum of 3 to a maximum of 40, about 3 to about 6,about 18 to about 36, about 6 to about 12, about 9 to about 18, about 16to about 20, or about 18 dosage units. The number of analgesic (e.g.,NSAID) dosage units may be the same as or different from the number ofthe antihistamine dosage units. In one embodiment, the number ofanalgesic (e.g., NSAID) dosage units is the same as the number of theantihistamine dosage units. In another embodiment, the combinationproduct provides a dose including two analgesic (e.g., NSAID) dosageunits and one antihistamine dosage unit.

In one embodiment, the oral combination composition includes: (i) 16-20analgesic (e.g., ibuprofen) dosage units, each containing about 50 mg toabout 800 mg of ibuprofen, or a pharmaceutically acceptable saltthereof; and (ii) 16-20 chlorpheniramine dosage units, each containingabout 1 mg to about 8 mg of chlorpheniramine, or a pharmaceuticallyacceptable salt thereof, wherein the dosage units are suitable foradministering 2-6 times per day, and wherein the analgesic (e.g.,ibuprofen) oral dosage units and the chlorpheniramine oral dosage unitsare substantially free of an additional synthetic active agent.

In another embodiment, the oral combination composition includes: 16-20dosage units, each containing about 50 mg to about 800 mg of analgesic(e.g., ibuprofen) and about 1 mg to about 8 mg of chlorpheniramine,wherein the dosage units are suitable for administering 3-6 times perday, and wherein said oral dosage units are substantially free of anadditional synthetic active agent.

In another embodiment, the oral combination composition includes: aminimum of 3 and a maximum of 40 oral dosage units, wherein each oraldosage unit comprises an OTC analgesic (e.g., NSAID) dose and anantihistamine dose, wherein the oral dosage units are substantially freeof an additional synthetic active agent.

In yet another embodiment, the oral combination composition includes:(i) a minimum of 3 and a maximum of 40 analgesic (e.g., NSAID) oraldosage units, wherein each analgesic (e.g., NSAID) oral dosage unitcomprises a dose of an analgesic (e.g., NSAID); and (ii) a minimum of 3and a maximum of 40 antihistamine oral dosage units, wherein eachantihistamine oral dosage unit comprises a dose of an antihistamine,wherein the analgesic (e.g., NSAID) and antihistamine oral dosage unitsare substantially free of an additional synthetic active agent. In oneembodiment, the oral combination composition product includes: (i) aminimum of 4 and a maximum of 32 non-steroidal anti-inflammatory drugoral dosage units; and (ii) a minimum of 4 and a maximum of 16antihistamine oral dosage units.

In another embodiment, the oral combination composition productincludes: (i) a minimum of 4 and a maximum of 16 non-steroidalanti-inflammatory drug oral dosage units each comprising about 200 mgibuprofen; (ii) a minimum of 4 and a maximum of 16 antihistamine oraldosage units each comprising 2-4 mg chlorpheniramine; and (iii) aminimum of 4 and a maximum of 16 non-steroidal anti-inflammatory drugoral dosage units each comprising about 100 mg ibuprofen.

In one embodiment, the oral combination composition includes: (i) afirst oral dosage unit comprising about 600 mg of an analgesic (e.g.,ibuprofen), or a therapeutically equivalent amount of a pharmaceuticallyacceptable salt thereof; and (ii) a second oral dosage unit comprisingan antihistamine.

The dosage ranges provided herein are inclusive of the recited numbers.The term “about” as used herein is inclusive of, and in some embodimentsequal to, the recited number.

III. Kits including the Combination Composition

In one aspect, the combination composition is provided as part of a kitto facilitate a suitable dosing regimen for treating sunburn. Thecombination composition ad embodiments thereof are described above andare equally applicable to the kits provided herein. The kits can furtherinclude a dispensing apparatus configured to facilitate suitableadministration, suitable frequency, and/or suitable duration oftreatment. The suitability of the dispensing apparatus may be basedpartly or completely on the combination composition. Thus, the kit mayinclude a dispensing apparatus having a plurality of analgesic dosageunits and a plurality of antihistamine dosage units (e.g. combinationcompositions).

In some embodiments, the kit includes a dispensing apparatus including aplurality of analgesic dosage units (e.g. oral dosage units, parenteraldosage unites or topical dosage units) and a plurality of antihistaminedosage units (e.g. oral dosage units, parenteral dosage unites ortopical dosage units). The number of analgesic dosage units is equal tothe number of antihistamine oral dosage units. The dosage units aresubstantially free of an additional synthetic active agent. Thedispensing apparatus is configured to dispense, 2 to 6 times daily overnot more than a three day period, one or two analgesic oral dosage units(e.g. OTC analgesics dosage units) and one or two antihistamine oraldosage units approximately simultaneously, or one or two analgesicdosage units (e.g. oral dosage units, parenteral dosage unites ortopical dosage units) and one or two antihistamine dosage unites (e.g.oral dosage units, parenteral dosage unites or topical dosage units)sequentially.

In one embodiment of the kit, the analgesic is an NSAID (e.g.ibuprofen). The antihistamine may be chlorpheniramine. In anotherembodiment, the analgesic is an OTC analgesic. The dosage units may beoral dosage units.

The dispensing apparatus can include any packaging, overwrap, orreusable structure such as a bottle, canister, packeting (e.g., of thetype used to dispense Vitapak®), blister pack (e.g., unit or dosedispensing blister packs), snap-lid type dispenser (e.g., of the typeused for weekly pill organizers), automated dispensers (such as thosemanufactured by ePill), etc.

In one embodiment, the dispensing apparatus is configured to dispenseindividual dosage units (e.g., tablets). In another embodiment, thedispensing apparatus is configured to dispense a dose, which may includemore than one dosage unit. In another embodiment, the dispensingapparatus is configured to dispense a daily dose, which may include morethan one dose. In another embodiment, the dispensing apparatus isconfigured to dispense doses for the duration of treatment. Thedispensing apparatus can optionally include one or more partitions,perforations, or markings, etc. to compartmentalize dosage units, activeagents, single doses, daily doses, and/or treatment periods. Thedispensing apparatus can be configured to dispense adult doses only,pediatric doses only, or to be capable of dispensing adult and/orpediatric doses depending on the administration regimen.

In some embodiments, the dispensing apparatus is configured tofacilitate co-administration of both an analgesic (e.g., NSAID) and anantihistamine. The dispensing apparatus can be, for example, adispensing mechanism that ejects both active agents at once. Forexample, the dispensing apparatus can be a blister pack havingcombination blisters. A combination blister may eject both active agentsapproximately simultaneously, whether formulated together or separately.For example, each blister can contain both an NSAID dosage unit and anantihistamine dosage unit. Alternatively, each blister could contain acombination dosage unit containing both the NSAID and the antihistamine.In either case, dispensing one active agent would also dispense thesecond active agent. (See FIG. 2.) The combination blister mayoptionally include a partition to compartmentalize an NSAID dosage unitand an antihistamine dosage unit to prevent interaction, friction, orother degradation during transport.

In another embodiment, the kit or dispensing apparatus can eject theactive agents separately. In one embodiment, each active agent iscontained in an independent blister pack with detailed instructions forcombined dosing (FIG. 5). In another embodiment, each blister containsone active agent, but the blister pack contains both active agents. Thisdispensing apparatus preferably includes one or more partitions,perforations, or markings to encourage co-administration of both activeagents. For example, the dispensing apparatus can be a blister packwherein each active agent is confined within a distinct blister, but theblisters are aligned, grouped, or otherwise configured to encourage thesubject to dispense both active agents (or otherwise indicate to thesubject that both active agents should be co-administered). For example,the blisters can be clustered in groups including at least one NSAIDblister containing an NSAID and at least one antihistamine blistercontaining an antihistamine. The blisters can be arranged (e.g., in rowsand columns), partitioned, perforated, or marked to designate individualdoses, daily doses, or treatment regimens. (See FIG. 1.)

In some embodiments, the dispensing apparatus can be configured tofacilitate suitable frequency of duration. The dispensing apparatus caninclude text, label, configuration, size, shape, marking, perforation,or other indicator to facilitate a suitable frequency of duration (e.g.,2-6 doses of the combination composition within a 24 hour period). (SeeFIG. 3.) This can be accomplished by providing a single packagecontaining doses for a single 24 hour period, or it can be accomplishedby marking or perforating the package to indicate the daily dose of thecombination composition.

In some embodiments, the dispensing apparatus can be configured tofacilitate suitable duration of treatment. The dispensing apparatus caninclude text, label, configuration, size, shape, marking, perforation,or other indicator to facilitate an entire treatment regimen (e.g.,including the doses for 3 to 6 days as described above). This can beaccomplished by providing a single package containing doses for theentire treatment period (see FIG. 3), or it can be accomplished bymarking or perforating the package to indicate the treatment dose of thecombination composition.

The dispensing apparatus may also be configured to dispense one or twofirst oral dosage units and one or two second oral dosage unitsapproximately simultaneously, or one or two first oral dosage units andone or two second oral dosage units sequentially.

In some embodiments, the kit includes a blister pack and the combinationcomposition. Thus, the dispensing apparatus may be a blister pack.

In one embodiment, the blister pack includes at least one analgesic(e.g., NSAID) blister and at least one antihistamine blister, preferablya plurality of NSAID blisters and a plurality of antihistamine blisters.In one embodiment, each blister contains a single dosage unit. In oneembodiment, the number of analgesic (e.g. NSAID) blisters and the numberof antihistamine blisters are independently selected from about 4 toabout 24, about 6 to about 20, about 10 to about 20, about 16 to about20, or about 18 blisters. In one embodiments, the number of analgesic(e.g. NSAID) blisters and the number of antihistamine blisters are thesame.

In another embodiment, the blister pack includes at least onecombination blister, preferably a plurality of combination blisters. Thenumber of combination blisters can be about 1 to about 40, about 3 toabout 6, about 18 to about 36, about 6 to about 12, about 9 to about 18,about 16 to about 20, or about 18 blisters.

In one embodiment, the kit includes 18 analgesic (e.g. NSAID) blistersand 18 antihistamine blisters. In some embodiments, each analgesicblister contains a 200 mg ibuprofen oral dosage form. In someembodiments, each antihistamine blister contains 2 mg chlorpheniramine.In other embodiments, the kit includes 18 analgesic (e.g. NSAID) and 18antihistamine combination blisters. In some related embodiments, the kitincludes 18 combination blisters each containing 200 mg ibuprofen and 2mg chlorpheniramine.

In one embodiment, the kit includes 18 analgesic (e.g. NSAID) blistersand 18 antihistamine blisters. In some embodiments, each analgesicblister contains a 200 mg or 400 mg ibuprofen oral dosage form. In someembodiments, each antihistamine blister contains 2 mg or 4 mgchlorpheniramine. In other embodiments, the kit includes 18 analgesic(e.g. NSAID) and 18 antihistamine combination blisters. In some relatedembodiments, the kit includes 18 combination blisters each containing200 mg or 400 mg ibuprofen and 2 mg or 4 mg chlorpheniramine.

The kit may further include text, label, configuration, size, shape,marking, perforation, or other indicator to facilitate theadministration of 1-2 analgesic (e.g. NSAID) dosage units and 1-2antihistamine dosage units approximately simultaneously. The kit mayfurther include text, label, configuration, size, shape, marking,perforation, or other indicator to facilitate dosing about every 4-12,4-8, 4-6, or about 4 hours. Likewise, the kit may further include text,label, configuration, size, shape, marking, perforation, or otherindicator to facilitate dosing two times per day (BID), three times perday (TID), four times a day (QID), five time per day, or six times perday. The kit may further include text, label, configuration, size,shape, marking, perforation, or other indicator to facilitate dosing forabout 3 to about 6 days, preferably about 3 consecutive days.

IV. Methods of Treating Sunburns

Methods of treating a sunburn in a subject, particularly a humansubject, in need of such treatment, are also provided. The methodincludes administering to the subject a combined therapeuticallyeffective amount of an analgesic (e.g., NSAID) and an antihistamine. Theanalgesic and antihistamine may be administered as a combinationcomposition as described above. Thus, the combination compositionsdescribed above, including all embodiments thereof, are equally usefulfor the methods provided herein.

In one embodiment, there is provided a method of treating a sunburn in asubject, e.g., a human subject, in need of such treatment which includesadministering to the subject a combined therapeutically effective amountof an analgesic and an antihistamine.

In one embodiment, the analgesic (e.g. OTC analgesic) is acetaminophenor an NSAID. In another embodiment, the OTC analgesic is an NSAID. Inanother embodiment, the NSAID is an aspirin, an ibuprofen, a naproxen,or a pharmaceutically acceptable salt thereof. In one embodiment, theNSAID is an ibuprofen, or a pharmaceutically acceptable salt thereof.

The antihistamine may be an H1-receptor antagonist antihistamine. TheH1-receptor antagonist antihistamine may be a diphenhydramine, aloratadine, a desloratadine, a meclizine, a quetiapine, a fexofenadine,a pheniramine, a cetirizine, a promethazine, a chlorpheniramine, alevocetirizine, or a pharmaceutically acceptable salt thereof. In oneembodiment, the antihistamine is a chlorpheniramine, or apharmaceutically acceptable salt thereof.

The antihistamine and analgesic (e.g. combination composition) may beadministered after the subject is exposed to UV radiation. Exemplarysources of UV radiation include, but are not limited to, natural sourcessuch as sunlight, and artificial sources such as lasers, lamps, andtanning booths (e.g. natural sunlight or solar simulator). In oneembodiment, the subject has been exposed to natural sunlight. In someembodiments, the duration of UV exposure is more than about 5 minutes,10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 2 hours, 5hours, or 10 hours. Thus, administering may be performed after exposureof the subject to ultraviolet radiation, e.g., after at least 0.25, 0.5,1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24 hours, or even longer. In someembodiments, the administering is at least about 1, 2, 3, 5, 8, 10, 12,24, or 48 hours after UV exposure. The administering may also be about 3to about 5 hours after UV exposure (e.g. natural sunlight exposureleading to sunburn). The administering may also be performed at leasttwo hours after exposure of the subject to ultraviolet radiation.

In another embodiment, the administering is performed after appearanceof one or more symptom(s) of sunburn in the subject. Exemplary burnsymptoms include, but are not limited to, erythema (redness), pain,edema (swelling), itching, peeling, rash, blistering, warmth, nausea,headache, and fever.

The term “sunburn” is used herein according to its generally acceptedmeaning in the art. A sunburn to skin is understood to result fromoverexposure to ultraviolet (UV) radiation. In one embodiment, thesunburn is a first degree burn. In another embodiment, the subject inneed of treatment has a sunburn that is a superficial (extending to thepapillary dermis) or deep (extending to the reticular dermis) seconddegree burn. In yet another embodiment, the subject in need of treatmenthas sunburn that is a third degree burn. In another embodiment, thesubject has a sunburn that is a fourth degree burn. For more severeburns (third and fourth degree), parenteral routes (e.g., IV) ofadministration may be desirable on an in-patient or out-patient basis.Thus, in some embodiments, the sunburn is an acute sunburn. The term“acute sunburn” is used according to its generally understood meaning inthe art.

In some embodiments, the administering is conducted about every 24, 23,22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2or 1 hour(s). In one embodiment, the administering is about every 24,12, 8, 6, or 4 hours. In yet another embodiment, the administering isabout every 8 or 12 hours. In some embodiments, the administering isabout 2, 3, 4, 5, or 6 times during at least one 24 hour period. Inanother embodiment, the administering is about 2 or 3 times during atleast one 24 hour period. In some embodiments, the administering is twotimes per day (BID), three times per day (TID), four times a day (QID),five time per day, or six times per day.

In one embodiment, the administering is orally administering. In anotherembodiment, the administering is topically administering. In anotherembodiments, the administering is parenterally administering.

In one embodiment, the method includes orally administering at least oneactive agent. In another embodiment, the method includes orallyadministering both the analgesic (e.g., NSAID) and the antihistamine. Inother embodiments, the antihistamine and/or analgesic are/is topicallyadministered.

In some embodiments, the method of treating a sunburn in a subject is amethod of decreasing recovery time from a sunburn. In some embodiments,the method of treating a sunburn in a subject is a method of relievingpain (e.g. temporarily) and/or relieving discomfort (e.g. temporarily)resulting form a sunburn (e.g. a mild to moderate or acute sunburn). Insome embodiments, the method of treating a sunburn in a subject is amethod of relieving redness (e.g. temporarily) in the skin of a subjectresulting from a sunburn (e.g. a mild to moderate or acute sunburn).

Pain and comfort may be assessed using known means in the art such as byusing a visual analog scale (VAS) method. The efficacy of thecombination compositions may be determined by comparing the pain asubject reports at various time intervals after drug and/or placeboadministration. Efficacy may be determined by comparing the painreported after treatment with the combination compositions to placebo ina crossover model. Erythema may be measured using conventional means inthe art. Efficacy of the combination compositions may be determined bycomparing the erythema reported after treatment with the combinationcompositions to that after placebo treatment in a crossover model.

Several embodiments of the invention are specifically described herein.Embodiments described in one section of this application are equallyapplicable to all other sections of the applications where appropriate.For examples, all embodiments of the combination compositions areequally applicable to the kits and methods provided herein. Likewise,the dosages and administrations are equally applicable to the kits andmethods. Moreover, for example, embodiments of the kits are equallyapplicable to the methods and vice versa.

The disclosures of all references and publications cited above areexpressly incorporated by reference in their entireties to the sameextent as if each were incorporated by reference individually.

To further illustrate particular embodiments, the following non-limitingexamples are provided.

EXAMPLES Example 1 Combination Composition for Treating Sunburn

Combination compositions were prepared including ibuprofen as theover-the-counter analgesic and chlorpheniramine as the antihistamine.The combination compositions were prepared according to the followingdosage levels:

TABLE 2 Combination Composition Dosages Dosage Chlorpheniramine (mg)Ibuprofen (mg) D1 4 200 D2 4 400 D3 4 600 D4 2 600 D5 4 800 D6 8 800

The active agents were individually formulated, but administeredsimultaneously or nearly simultaneously.

Example 2 Study Demonstrating Efficacy in Treating Sunburn

Each of the combination composition dosages described in the precedingExample was administered to at least one volunteer to assess itsefficacy in treating sunburn. The results are provided in the followingtable.

The average time to first reported onset of relief was about 45 minutesat each dosage level. Notably, each subject reported complete recoveryin no more than 3 days.

TABLE 3 Study Results Symptoms Prior to Treatment Freq. Heat & AfterTreatment Subject Age of Complexion Surface Stinging & Burn AssessmentNumber Grp Dosage Dose Type Area Severity Pain Edema Itching ErythemaSensation Day 1 Day 2 Day 3 1 Child D1 ~6 hr F H S 3+ 3+ 3+ 3+ 3+ 2+ 1+0 2 Child D1 ~6 hr M H S 3+ 2+ 3+ 3+ 2+ 2+ 1+ 0 3 Adult D2 ~6 hr F H S3+ 3+ 3+ 3+ 3+ 2+ 1+ 0 4 Adult D2 ~6 hr F H S 3+ 3+ 3+ 3+ 3+ 2+ 1+ 0 5Adult D2 ~6 hr F H S 3+ 3+ 3+ 3+ 3+ 2+ 1+ 0 6 Adult D2 ~6 hr M M S 3+ 3+3+ 3+ 3+ 2+ 0   0* 7 Adult D2 ~6 hr M M S 3+ 2+ 3+ 3+ 2+ 2+ 0   0* 8Adult D3 ~6 hr F H S 3+ 3+ 3+ 3+ 3+ 2+ 1+ 0 9 Adult D3 ~6 hr F H S 3+ 3+3+ 3+ 3+ 2+ 1+ 0 10 Adult D4 ~6 hr F H S 3+ 3+ 3+ 3+ 3+ 2+ 1+ 0 11 AdultD5 ~6 hr F H S 3+ 3+ 3+ 3+ 3+ 2+ 1+ 0 12 Adult D6 ~8 hr F H S 3+ 3+ 3+3+ 3+ 2+ 1+ 0 13 Adult D6 ~8 hr F H S 3+ 3+ 3+ 3+ 3+ 2+ 1+ 0 14 Adult D6~8 hr M H S 3+ 3+ 3+ 3+ 3+ 2+ 1+ 0 Complexion Type: Fair (F), Medium(M), Dark (D). Surface Area: High (H) ≧75%, Medium (M) ≧50% to ≦75%, Low(L) ≦50%. Severity: S (Severe), Moderate (Mo), Mild (Mi). Pain, Edema,Stinging & Itching, Erythema, and Heat & Burn Sensation: High (3+),Medium (2+), Low (+). After Treatment Assessment: Uncomfortable (3+):inability to sleep or wear clothing and/or discomfort in dailyactivities; Comfortable (2+): ability to sleep, wear clothing, andperform daily function with minimal discomfort; Decreased sensitivityand enhanced comfort (1+); Complete recovery (0): no pain, edema,stinging and itching, erythema, or hot and burning sensation. *Including2 subjects reporting complete recover on Day 2.

1. A method of treating a sunburn in a subject in need of suchtreatment, said method comprising administering to said subject acombined therapeutically effective amount of an over-the-counteranalgesic and an antihistamine.
 2. (canceled)
 3. (canceled) 4.(canceled)
 5. The method of claim 1, wherein said over-the-counteranalgesic is a non-steroidal anti-inflammatory drug, and saidnon-steroidal anti-inflammatory drug is an ibuprofen, or apharmaceutically acceptable salt thereof.
 6. (canceled)
 7. (canceled) 8.The method of claim 1, wherein said antihistamine is a chlorpheniramine,or a pharmaceutically acceptable salt thereof.
 9. (canceled) 10.(canceled)
 11. (canceled)
 12. (canceled)
 13. (canceled)
 14. (canceled)15. The method of claim 1, wherein said administering is orallyadministering.
 16. A kit for the treatment of a sunburn comprising: adispensing apparatus comprising a plurality of over-the-counteranalgesic oral dosage units and a plurality of antihistamine oral dosageunits, wherein the number of over-the-counter analgesic oral dosageunits is equal to the number of antihistamine oral dosage units, whereinsaid the oral dosage units are substantially free of an additionalsynthetic active agent, and wherein the dispensing apparatus isconfigured to dispense, 2 to 6 times daily over not more than a threeday period, (i) one or two over-the-counter analgesic oral dosage unitsand one or two antihistamine oral dosage units approximatelysimultaneously, or (ii) one or two over-the-counter analgesic oraldosage units and one or two antihistamine oral dosage unitssequentially.
 17. The kit of claim 16, wherein the over-the-counteranalgesic is a non-steroidal anti-inflammatory drug.
 18. An oralcombination composition product for treatment of a sunburn in a subjectin need of such treatment comprising: (i) 16-20 ibuprofen dosage units,each containing about 50 mg to about 800 mg of ibuprofen, or apharmaceutically acceptable salt thereof; and (ii) 16-20chlorpheniramine dosage units, each containing about 1 mg to about 8 mgof chlorpheniramine, or a pharmaceutically acceptable salt thereof,wherein the dosage units are suitable for administering 2-6 times perday, and wherein said ibuprofen oral dosage units and saidchlorpheniramine oral dosage units are substantially free of anadditional synthetic active agent.
 19. An oral combination compositionproduct for treatment of a sunburn in a subject in need such treatmentcomprising: 16-20 dosage units, each containing about 50 mg to about 800mg of ibuprofen and about 1 mg to about 8 mg of chlorpheniramine,wherein the dosage units are suitable for administering 3-6 times perday, and wherein said oral dosage units are substantially free of anadditional synthetic active agent.
 20. An oral combination compositionproduct for treatment of a sunburn in a subject in need of suchtreatment comprising: a minimum of 3 and a maximum of 40 oral dosageunits, wherein each oral dosage unit comprises a non-steroidalanti-inflammatory drug dose and an antihistamine dose, and wherein theoral dosage units are substantially free of an additional syntheticactive agent.
 21. An oral combination composition product for treatmentof a sunburn in a subject in need of such treatment comprising: (i) aminimum of 3 and a maximum of 40 non-steroidal anti-inflammatory drugoral dosage units, wherein each non-steroidal anti-inflammatory drugoral dosage unit comprises a dose of a non-steroidal anti-inflammatorydrug; and (ii) a minimum of 3 and a maximum of 40 antihistamine oraldosage units, wherein each antihistamine oral dosage unit comprises adose of an antihistamine, wherein the non-steroidal anti-inflammatorydrug and antihistamine oral dosage units are substantially free of anadditional synthetic active agent.
 22. (canceled)
 23. The oralcombination composition of claim 21, comprising: (i) a minimum of 4 anda maximum of 16 non-steroidal anti-inflammatory drug oral dosage unitseach comprising about 200 mg ibuprofen; (ii) a minimum of 4 and amaximum of 16 antihistamine oral dosage units each comprising 2-4 mgchlorpheniramine; and (iii) a minimum of 4 and a maximum of 16non-steroidal anti-inflammatory drug oral dosage units each comprisingabout 100 mg ibuprofen.
 24. (canceled)
 25. The oral combinationcomposition of claim 21, wherein said non-steroidal anti-inflammatorydrug is a racemic ibuprofen, or a pharmaceutically acceptable saltthereof.
 26. The oral combination composition of claim 21, wherein saidantihistamine is an H₁-receptor antagonist antihistamine.
 27. (canceled)28. The oral combination composition of claim 26, wherein saidantihistamine is a chlorpheniramine, or a pharmaceutically acceptablesalt thereof.
 29. (canceled)
 30. An oral dosage unit comprising about600 mg of a racemic ibuprofen, or a therapeutically equivalent amount ofa pharmaceutically acceptable salt thereof, and an antihistamine. 31.(canceled)
 32. The oral dosage unit of claim 30, wherein saidantihistamine is a chlorpheniramine, or a pharmaceutically acceptablesalt thereof.
 33. The oral dosage unit of claim 32, wherein said oraldosage unit comprises about 4 mg of said chlorpheniramine, or atherapeutically equivalent amount of a pharmaceutically acceptable saltthereof.
 34. An oral combination composition comprising: (i) a firstoral dosage unit comprising about 600 mg of an ibuprofen, or atherapeutically equivalent amount of a pharmaceutically acceptable saltthereof; and (ii) a second oral dosage unit comprising an antihistamine.35. (canceled)
 36. The oral combination composition of claim 34, whereinsaid antihistamine is a chlorpheniramine, or a pharmaceuticallyacceptable salt thereof.
 37. The oral combination composition of claim34, wherein said second oral dosage unit comprises about 4 mg of saidchlorpheniramine, or a therapeutically equivalent amount of apharmaceutically acceptable salt thereof.